The present invention relates to valuable new forms of a chiral fluoroquinolone, viz. arginine salt forms thereof, a novel process for manufacturing the novel arginine salt forms of the chiral fluoroquinolone, the use of the novel forms of the arginine salt of the chiral fluoroquinolone in the manufacture of pharmaceutical formulations and the use of the novel forms of the arginine salt of the chiral fluoroquinolone in medicine. More particularly, it relates to arginine salt forms of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij] quinolizine-2-carboxylic acid, a process for preparing the same and their use in pharmaceutical formulations and medicine.
The chiral fluoroquinolone known under the name S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid is described in JP Patent 63,192,753A, JP Patent 05,339,238A, and in our pending U.S. patent applications Ser. Nos. 09/566,875 and 09/640,947, WO 00/68229 and PCT Application No. PCT/IN00/00111.
S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid is an optically active isomer of the racemic compound which is claimed in U.S. Pat. No. 4,399,134. Although S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid is not presently an ingredient of any commercial product, it is potentially useful as a commercial antimicrobial agent.
S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid has an aqueous solubility of 0.8-2.0 mg/ml over the pH range 8.0-9.5 at 28xc2x0 C., thus creating problems in having to formulate the drug as a tablet or capsule, or in making formulations for gavage and parenteral injection. The need for a salt is clearly indicated, as the lack of an appropriate salt form can hinder the development of dosage forms acceptable for systemic use in mammals.
S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo [i,j]quinolizine-2-carboxylic acid has a pKa value of 6.80 suggesting a weak acid character and thus an ability to form a salt with an appropriate base. Generally, conversion of a pharmacologically active compound into a salt form induces a change in the compound""s physicochemical properties such as solubility, absorption velocity, etc. Pharmaceutically more desirable salt forms may be selected by studying whether or not a crystalline or amorphous form, or polymorph or pseudopolymorph can be produced, and determining the properties including its physicochemical or biological properties. A pseudopolymorph is a polymorph that differs from a true polymorph by the incorporation of solvent (Solid-state Chemistry of Drugs, 2nd Ed. S. R. Byrn et al (Eds). SSCI, Inc. 1999, p-514).
Pharmaceutically acceptable salts of racemic 9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid such as salts with inorganic bases and organic bases are mentioned in the text of Otsuka""s U.S. Pat. No. 4,399,134. Besides salts with inorganic bases and organic bases, amino acid salts of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid are identified in our pending U.S. patent applications Ser. Nos. 09/566,875 and 09/640,947, WO 00/68229 and PCT Application No. PCT/IN00/00111. The subject matter of these applications is incorporated herein by reference.
S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid, L-arginine salt 0.25 hydrate and S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperin-1-yl)-5-methyl-1-oxo-1H, 5H-benzo [i,j]quinolizine-2-carboxylic acid, L-arginine salt, 0.75 hydrate described in Examples 7 and 8 of U.S. patent applications Ser. Nos. 09/566,875 and 09/640,947, WO 00/68229 and PCT Application No. PCT/IN00/00111 respectively are highly hygroscopic and turn into syrups on exposure at a relative humidity of 41%. This presents major problems in bulk or manufacturing scale. Many hydrates and salts associated with water are susceptible to changes in humidity, are hygroscopic under adverse storage conditions and during pharmaceutical processing of them to medicament forms.
Amino acid salts, inorganic base and alkali salts and organic base salts of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo [i,j] quinolizine-2-carboxylic acid were prepared and studied by the inventors and it was found that:
(a) the arginine salt may exist in either a substantially crystalline form or a substantially amorphous form, each form having distinctive physicochemical, solubility and stability properties;
(b) the arginine salt is less prone than the sodium salt to absorb moisture at specified humidity levels;
(c) the arginine salt, whether crystalline or amorphous, possesses a lower propensity to cause phlebitis than the sodium and potassium salts as determined in rats by intravenous administration; and
(d) the arginine salt is less toxic in rodents than the alkali salt forms.
In summary, the substantially crystalline form and substantially amorphous form of the arginine salt of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid have been found by the inventors to have very desirable properties in possessing under specified conditions, less hygroscopicity, favourable aqueous solubility, a low propensity to cause phlebitis, and favourable acute toxicity values. These forms are expected to be very useful as pharmaceutical agents as compared with the sodium salt, other inorganic base/alkali salts, organic base salts and other aminoacid salts. These advantages will be apparent from the experimental data shown hereafter.
The main objective of the invention accordingly relates to new arginine salts of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid of the formula I 
in which x denotes 0, 0.25, 0.5, 0.75, or 1.0, compositions comprising these salts, methods for preparing these salts and their use in medicine.
Another object of the present invention is to provide novel forms of the arginine salt of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid which can be used in full scale manufacturing of pharmaceutical formulations.
Still another object of the present invention is to provide a process for bulk scale production of S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo [i,j] quinolizine-2-carboxylic acid arginine salts of this invention.
A further object of the present invention to provide antibacterial compositions comprising the S-(xe2x88x92)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt forms as an active component.